Project 3: Project Summary Epithelial ovarian cancer is comprised of several subtypes differentiated by histology and molecular composition, with varying levels of platinum sensitivity based on specific histology. High grade serous carcinoma (HGSC) is the most common and is sensitive to platinum drugs and poly (ADP ribose) polymerase (PARP) inhibitors. However, with subsequent exposure to treatment, recurrent HGSC becomes increasingly platinum and PARP inhibitor resistant. Additionally, other histologic subtypes such as low grade serous and mucinous ovarian cancers, sometimes RAS mutated, often display platinum resistance at initial diagnosis, and new treatment strategies are needed for these patients whose cancers are either RAS mutated or RAS wild-type. The overall objective of this proposal is to investigate the clinical efficacy of a combination therapy targeting the Ras-ERK pathway serine threonine kinase MEK and two anti-apoptotic proteins, BCL2 and BCLXL. Based on evidence that the RAS-ERK pathway is activated in a large percentage of ovarian cancers and evidence of efficacy of combined MEK- BCL-2/XL inhibition in (1) preclinical PDX models of chemoresistant high grade serous ovarian cancer (HGSC), (2) preclinical studies showing efficacy of combined MEK and BCL-2/XL inhibition in Ras mutant tumors, and (3) a Phase 1 clinical trial showing safety and tolerability of combined treatment with trametinib (MEK inhibitor) and navitoclax (BCL-2/XL inhibitor), we hypothesize that combination MEK and BCL-2/XL inhibition will have activity in refractory/relapsed ovarian cancer. To test this hypothesis, we will carry out a phase II clinical trial to test the efficacy of combined treatment with trametinib and navitoclax in recurrent platinum-resistant and refractory HGSOC and low grade serous cancer in addition to ovarian cancers harboring alterations in Ras and Raf pathway genes. An active and ongoing study, Dana-Farber/Harvard Cancer Center (DF/HCC) Protocol 13-505 (CTEP 9525 supported by U01CA062490, NCT02079740) is a phase 1 study that has tested the combination of the oral MEK inhibitor trametinib with the oral BCL-2 XL inhibitor navitoclax. This trial has been open to accrual since March 2014, has tested different dose schedules, and has established a recommended phase 2 dose (RP2D). This RP2D from CTEP 9525 will be used in our Phase II study, proposed in this project, and is entitled ?A Phase 2 study of combination trametinib and navitoclax in recurrent ovarian cancer.? We will investigate genetic and proteomic markers that correlate with efficacy. In addition, we will investigate therapeutic approaches to enhance the efficacy of this combination in pre-clinical studies. These studies promise to provide information critical to the identification of a new therapeutic strategy to treat resistant ovarian cancers, which if effective, could potentially extend the lives of patients with recurrent ovarian cancer.